Invasive aspergillosis is a common fungal infection in immunocompromised patients and carries a poor prognosis. A thorough understanding of the components of the immune response to invasive aspergillosis in the context of an immunocompromised host is important, because it may lead to the development of new treatments aimed at improving the host defense against this infection. In the last funding period, we established NK cells to be critical to defense against the infection in the neutropenic host and demonstrated NK cells to be the major source of interferon- (IFN-) early in the infection. Our preliminary studies for the current proposal indicate that NK cell activation is beneficial to the host, that NK cell-derived IFN- mediates the lung expression of the chemokine ligands CXCL9, CXCL10, and CXCL11, and that effector leukocytes expressing CXCR3, the receptor for these ligands, traffic to the lung in invasive aspergillosis are essential for host defense in invasive aspergillosis. We therefore hypothesize that activation of NK cells and NK cell induction of the interferon--inducible ELR-negative CXC chemokines are critical to host defense in invasive aspergillosis. We propose to test these hypotheses under the following specific aims: 1) To examine the mechanism of NK cell activation in host defense in invasive aspergillosis; 2) To investigate the role of NK cells in mediating the lung expression of interferon gamma-inducible CXC chemokines in invasive aspergillosis; and 3) To determine the role of interferon gamma-inducible CXC chemokines in host defense against invasive aspergillosis. We propose to use transgenic and gene knockout animals in a mouse model of invasive aspergillosis, in vivo cell depletion and adoptive transfer strategies, and in vitro immunologic techniques to achieve these goals. The proposed studies are relevant to public health in that they should define previously unrecognized host defense mechanisms in an important human illness, with the prospect that these mechanisms could be manipulated therapeutically to benefit patients.